Neurodegenerative diseases leading to dementia are a tremendous societal burden, currently devastating 9 million people domestically and 47 million people worldwide. Current inability to effectively prevent, diagnose and combat neurodegeneration results in staggering direct and indirect costs Alzheimer's disease (AD), the most common cause of dementia, alone afflicts over 5 million Americans and accounts for the 6th leading cause of death in the USA. AD requires an estimated 18 billion hours of unpaid caretaking and well over $250 billion of medical costs annually. Prevalence of the disease is projected to escalate to nearly 14 million people domestically and 135 million worldwide by 2050, with no potential cure in immediate sight. There is a dire need for technological advancements toward diagnostics, prevention, therapeutics and eventual cures that will each have profound beneficial impacts on the population.
Current clinical evaluation typically includes non-invasive brain imaging with magnetic resonance imaging (MRI), positron emission tomography (PET), or other advanced imaging strategies which provide insight into tissue volume changes, chemical composition, cortical metabolic rate, alterations associated with tissue cellularity and disease biomarkers, and structural abnormalities attributed to neurodegenerative disease. To aid in the diagnosis of AD and differential diagnosis from non-Alzheimer dementias, fluorodeoxyglucose (FDG) PET and amyloid PET reveal AD-associated patterns of cerebral cortical metabolism and beta amyloid deposits in the gray matter, respectively. Similarly, tau PET reveals neurofibrillary tangles in the brain. However, due to a lack of advancement in analysis technologies, meaningful use of these imaging techniques for neurodegenerative disease is restricted to late stages when considerable tissue damage and cognitive or other clinical abnormalities are present. As we deepen our understanding of the multiplicity of abnormalities associated with AD, there is increasing evidence that the continual targeting of these amyloid plaques and neurofibrillary tangles may merely be treating late stage symptoms rather than the underlying causes. The inability to effectively detect early stages of AD precludes pre-symptomatic intervention and conceals the potential beneficial effects of drug candidates.
Implicit to the neurodegenerative process is the death of the signaling nerve cells in the brain, though this can merely be the ultimate consequence in a cascade of degeneration within brain tissue. The structural integrity of tissue is necessary for neuron support and survival and clearance of molecular waste that must be removed from the brain for maintenance of neural tissue homeostasis and efficient function. Alterations in non-cellular components of the brain are complicit in the degenerative process and may be a precursor of lost nerve cell function. It has been shown that proper regulation of neural tissue homeostasis is necessary for eliminating toxic residue buildup, a process that can be altered in the AD brain. Yet, there remains limited understanding of brain structural content and its impact on transport of molecules in the brain interstitium. Currently, the clinical use and the diagnostic capacity of brain MRI remains limited to differential diagnosis, only after symptomatic presentation, principally due to the inherently low spatial resolution—MRI image voxels are in mm dimensions, whereas structural changes contributing to tissue degeneration originate at the sub-micron scale. FDG, amyloid, and tau PET scans suffer from similar limitations.